Project Summary Osteoarthritis (OA) is the leading cause of disability worldwide, yet its treatment options remain limited, in part due to the lack of non-invasive techniques to quantify disease progression and response to therapies. We propose to develop simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) (PET/MR) using 18F-sodium fluoride (18F-NaF) to assess subchondral bone remodeling as a marker of early OA progression and relate bone metabolism to biochemical changes in articular cartilage. This approach will provide a considerable advance for imaging of OA; including new markers of early disease and insights into the spatial and temporal progression of OA. This project aims to develop a new approach to knee imaging using PET/MR, providing fast, quantitative and registered metabolic and biochemical markers sensitive to the earliest changes in OA. Our specific aims are (1) to develop parallel MR imaging techniques for fast and simultaneous bilateral knee MRI; (2) to create an automated attenuation correction method for flexible MRI knee coils to achieve accurate and reproducible dynamic scans of 18F-NaF PET uptake; and (3) to study the spatiotemporal relationships between bone remodeling and adjacent cartilage changes and evaluate if 18F-NaF PET can predict degenerative knee changes in subjects at risk of developing OA following anterior cruciate ligament (ACL) tears. The innovation of this work lies in the development of a novel imaging technique for studying OA, PET/MR, that offers quantitative and multimodal information sensitive to the earliest metabolic and biochemical changes in bone and cartilage. Advanced methods developed in this work will enhance fast, quantitative assessment of early disease biomarkers within each imaging modality. The significance of this work is that we will be able to sensitively and quantitatively track the earliest changes of OA, and study the spatiotemporal progression of disease. These contributions will provide new insights into OA pathogenesis, leading to new treatment targets, and ultimately therapies to arrest the onset and progression of OA.